In the literature, both heterogeneous and homogeneous catalysts have been reported to promote a hydrogen autotransfer process or hydrogen borrowing. Heterogeneous catalysts have some advantages over homogeneous ones, such as their greater ease of recovery from the reaction mixture. However, high pressures and temperatures are often required and, therefore, the use of homogeneous catalysts frequently allows reactions to occur at a lower temperature and with higher selectivity than heterogeneous catalysts.
Grigg and co-workers reported the first hydrogen borrowing reaction via homogeneous catalysis in 1981 (R. Grigg, T. R. B. Mitchell, S. Sutthivaiyakit and N. Tongpenyai, J. Chem. Soc. Chem. Commun., 1981, 611-812). The authors achieved the N-alkylation of amines by alcohols using metal-phosphine complexes generated in situ and preformed metal-phosphine catalysts. Iridium, ruthenium and rhodium complexes have been examined and the best results were obtained with preformed rhodium-phosphine complex, RhH(PPh3)4. The substrate scope was limited to relatively volatile alcohols only.
Since this first example reported by Grigg et al., a great effort has been made to develop better catalysts for the alkylation of amines. Several other complexes were synthesised and tested in hydrogen borrowing reactions. The catalysts which gave the best activities and yields included ruthenium-based catalysts.
In 1982 Murahashi and co-workers demonstrated that aliphatic amines were competent substrates for N-alkylation with alcohols using a [RuH2(PPh3)4] catalyst (S.-I. Murahashi, K. Kondo and T. Hakata, Tetrahedron Lett., 1982, 23, 229-232) and aryl amines with [RuCl2(PPh3)3]. The substrate scope in these two examples was still quite limited and the reaction conditions were harsh, requiring a high temperature (180° C.).
More recently, better catalytic systems have been reported. Williams and co-workers demonstrated that [Ru(p-cymene)Cl2]2, activated by the addition of either bis(diphenylphosphino)ferrocene (dppf) or DPEphos, was an active catalyst system for the alkylation of amines by primary alcohols (summarised in M. H. S. A. Hamid, C. L. Allen, G. W. Lamb, A. C. Maxwell, H. C. Maytum, A. J. A. Watson and J. M. J. Williams, J. Am. Chem. Soc., 2009, 131, 1766-1774). The addition of an additive, one of the phosphine ligands, was paramount to achieve good yield. When [Ru(p-cymene)Cl2]2 was used alone as the catalyst, the N-alkylation proceeded slowly. This catalytic system showed a broad tolerance of functional groups but it did not work when secondary alcohols were used as the substrate. The addition of a further ligand to promote the reaction is undesirable. Furthermore, the reliance on the additive to provide a viable reaction rate is undesirable. Therefore, it is an aim of certain embodiments of the present invention to remove the need for inclusion of additional ligands.
Beller and co-workers further improved this family of ruthenium complexes, reporting that [Ru3(CO)12] promotes the N-alkylation of primary and secondary amines using both primary and secondary alcohols (A. Tillack, D. Hollmann, D. Michalik and M. Beller, Tetrahedron Lett., 2006, 47, 8881-8885 and A. Tillack, D. Hollmann, K. Mevius, D. Michalik, S. Bähn and M. Beller, European J. Org. Chem., 2008, 4745-4750). To obtain higher yields, a phosphine ligand was added in a catalytic amount.
The dimeric iridium complex η5-(pentamethylcyclopentadienyl)iridium(III) dichloride [Cp*IrCl2]2, has also been applied in hydrogen borrowing (for a review, see K. Fujita and R. Yamaguchi, Synlett, 2005, 560-571). This iridium dimer has been efficaciously used in the N-alkylation of primary and secondary amines. Primary and secondary alcohols could be used, though with bulky substrates the catalyst loading was increased up to 5 mol % of iridium in order to obtain the products in high yield. Functional groups that could be tolerated were quite broad and included both electron-withdrawing and electron-donating groups, such as ethers, esters, halogens, nitro groups and nitrile groups.
Other iridium complexes, such as the dimer [Cp*IrI2]2, (SCRAM), have shown a better activity in protic solvents, such as water and t-amyl alcohol.
One of the first examples was the dimer [Cp*IrI2]2, (SCRAM), which gave good yields in water and proceeded without adding base (O. Saidi, A. J. Blacker, M. M. Farah, S. P. Marsden and J. M. J. Williams, Chem. Commun., 2010, 46, 1541-1543).
Recently, a monomeric iridium catalysthas showed high activity in the N-alkylation reaction using water as the solvent (R. Kawahara, K. Fujita and R. Yamaguchi, Adv. Synth. Catal., 2011, 353, 1161-1168). The substrate scope was broad; however, a high concentration is required (7 M) in order to achieve high yields and secondary alcohols could efficaciously be used only for the alkylation of primary amines.
In order to improve the activity of catalysts used in hydrogen borrowing new iridium complexes containing N-heterocyclic carbenes (NHCs) were investigated (A. da Costa, M. Viciano, M. Sanaú, S. Merino, J. Tejeda, E. Peris and B. Royo, Organometallics, 2008, 27, 1305-1309; A. Prades, R. Corberan, M. Poyatos and E. Peris, Chem.—A Eur. J., 2008, 14, 11474-11479; D. Gnanamgari, E. L. O. Sauer, N. D. Schley, C. Butler, C. D. Incarvito and R. H. Crabtree, Organometallics, 2009, 28, 321-325). The yields obtained with these catalysts were comparable to results obtained with [Cp*IrCl2]2, but the substrate scope was more limited.
Generally, the iridium dimer [Cp*IrCl2]2 is accepted to be a potent catalyst for hydrogen borrowing processes.
The present invention aims to provide alternative metal complexes preferably with improved catalytic activity. It is an aim of the present invention to provide a metal complex which has improved (i.e. reduced) loading of the metal complex in a catalytic reaction. It is also an aim of the present invention to increase the rate of catalytic reactions comprising a metal complex of the invention. The invention aims to achieve these improvements with a high tolerability to functional groups on substrates, substitution on substrates, primary or secondary alcohols and primary or secondary amines, the substrates, alcohols and amine being present in a catalytic reaction mediated by the metal complex of the invention. Prior art metal complexes have demonstrated limited tolerance to solvents. Therefore, the invention aims to provide metal complexes with catalytic activity in a range of solvents, such as in polar solvents, dipolar solvents and apolar solvents, for example water and other aprotic solvents, DMF, NMP or DMSO. Certain embodiments of the invention aim to potentially provide enantioselective methodologies to prepare chiral amines.
The present invention satisfies some or all of the above aims and overcomes problems of the prior art.